Yang Zhang1,2, Xiang Xu2, Yuxin Tong3, Xijie Zhou2, Jian Du2, In Young Choi4, Shouwei Yue1, Gabsang Lee4,5, Blake N Johnson3, Xiaofeng Jia6,7,8,9,10. 1. Department of Physical Medicine & Rehabilitation, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. 2. Department of Neurosurgery, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building 823, Baltimore, MD, 21201, USA. 3. Department of Industrial and Systems Engineering, School of Neuroscience, Virginia Tech, Blacksburg, 24061, VA, USA. 4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 6. Department of Neurosurgery, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF Building 823, Baltimore, MD, 21201, USA. xjia@som.umaryland.edu. 7. Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. xjia@som.umaryland.edu. 8. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. xjia@som.umaryland.edu. 9. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. xjia@som.umaryland.edu. 10. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. xjia@som.umaryland.edu.
Abstract
BACKGROUND: Severe peripheral nerve injury significantly affects patients' quality of life and induces neuropathic pain. Neural crest stem cells (NCSCs) exhibit several attractive characteristics for cell-based therapies following peripheral nerve injury. Here, we investigate the therapeutic effect of NCSC therapy and associated changes in the spinal cord in a sciatic nerve transection (SNT) model. METHODS: Complex sciatic nerve gap injuries in rats were repaired with cell-free and cell-laden nerve scaffolds for 12 weeks (scaffold and NCSC groups, respectively). Catwalk gait analysis was used to assess the motor function recovery. The mechanical withdrawal threshold and thermal withdrawal latency were used to assess the development of neuropathic pain. Activation of glial cells was examined by immunofluorescence analyses. Spinal levels of extracellular signal-regulated kinase (ERK), NF-κB P65, brain-derived neurotrophic factor (BDNF), growth-associated protein (GAP)-43, calcitonin gene-related peptide (CGRP), and inflammation factors were calculated by western blot analysis. RESULTS: Catwalk gait analysis showed that animals in the NCSC group exhibited a higher stand index and Max intensity At (%) relative to those that received the cell-free scaffold (scaffold group) (p < 0.05). The mechanical and thermal allodynia in the medial-plantar surface of the ipsilateral hind paw were significantly relieved in the NCSC group. Sunitinib (SNT)-induced upregulation of glial fibrillary acidic protein (GFAP) (astrocyte) and ionized calcium-binding adaptor molecule 1 (Iba-1) (microglia) in the ipsilateral L4-5 dorsal and ventral horn relative to the contralateral side. Immunofluorescence analyses revealed decreased astrocyte and microglia activation. Activation of ERK and NF-κB signals and expression of transient receptor potential vanilloid 1 (TRPV1) expression were downregulated. CONCLUSION: NCSC-laden nerve scaffolds mitigated SNT-induced neuropathic pain and improved motor function recovery after sciatic nerve repair. NCSCs also protected the spinal cord from SNT-induced glial activation and central sensitization.
BACKGROUND: Severe peripheral nerve injury significantly affects patients' quality of life and induces neuropathic pain. Neural crest stem cells (NCSCs) exhibit several attractive characteristics for cell-based therapies following peripheral nerve injury. Here, we investigate the therapeutic effect of NCSC therapy and associated changes in the spinal cord in a sciatic nerve transection (SNT) model. METHODS: Complex sciatic nerve gap injuries in rats were repaired with cell-free and cell-laden nerve scaffolds for 12 weeks (scaffold and NCSC groups, respectively). Catwalk gait analysis was used to assess the motor function recovery. The mechanical withdrawal threshold and thermal withdrawal latency were used to assess the development of neuropathic pain. Activation of glial cells was examined by immunofluorescence analyses. Spinal levels of extracellular signal-regulated kinase (ERK), NF-κB P65, brain-derived neurotrophic factor (BDNF), growth-associated protein (GAP)-43, calcitonin gene-related peptide (CGRP), and inflammation factors were calculated by western blot analysis. RESULTS: Catwalk gait analysis showed that animals in the NCSC group exhibited a higher stand index and Max intensity At (%) relative to those that received the cell-free scaffold (scaffold group) (p < 0.05). The mechanical and thermal allodynia in the medial-plantar surface of the ipsilateral hind paw were significantly relieved in the NCSC group. Sunitinib (SNT)-induced upregulation of glial fibrillary acidic protein (GFAP) (astrocyte) and ionized calcium-binding adaptor molecule 1 (Iba-1) (microglia) in the ipsilateral L4-5 dorsal and ventral horn relative to the contralateral side. Immunofluorescence analyses revealed decreased astrocyte and microglia activation. Activation of ERK and NF-κB signals and expression of transient receptor potential vanilloid 1 (TRPV1) expression were downregulated. CONCLUSION: NCSC-laden nerve scaffolds mitigated SNT-induced neuropathic pain and improved motor function recovery after sciatic nerve repair. NCSCs also protected the spinal cord from SNT-induced glial activation and central sensitization.
Authors: Jaquette Liljencrantz; Malin Björnsdotter; India Morrison; Simon Bergstrand; Marta Ceko; David A Seminowicz; Jonathan Cole; Catherine M Bushnell; Håkan Olausson Journal: Pain Date: 2012-11-05 Impact factor: 6.961
Authors: Jan Hoeber; Carl Trolle; Niclas Konig; Zhongwei Du; Alessandro Gallo; Emmanuel Hermans; Hakan Aldskogius; Peter Shortland; Su-Chun Zhang; Ronald Deumens; Elena N Kozlova Journal: Sci Rep Date: 2015-06-08 Impact factor: 4.996